四氫異喹啉生物鹼是一種具有良好活性的抗癌藥物，尤其以依特那斯汀743及沙弗拉黴素所具有的生物活性最好，以及其結構上所具有的特殊性，發展至今已經有三十年以上的歷史。雖然此類生物鹼具有良好的生物活性，卻無法在市面上販售，主要原因有二：(1)自然界萃取出的量太少，(2)以合成的方式製備，步驟過於繁複且不易處理；因此為了有效的改善上述問題，我們便以此類生物鹼的抗癌反應機制來設計抗癌藥物，以簡單快速的合成方法來得到具有抗癌活性的衍生物。本論文第一章，簡單介紹四氫異喹啉生物鹼的背景與抗癌機制，以及近幾年來的合成研究；第二章，描述以四氫異喹啉生物鹼的抗癌機制設計及合成目標產物，並探討其類似物的生物活性；第三章，利用控制比特－史賓格勒環化反應，進行單一環化，快速建立四氫異喹啉生物鹼的基本骨架。

The tetrahydroisoquinoline alkaloids have been studied thoroughly about their biological and chemical significance over the past 30 years. These natural products show great biological activity, especially ET-743 and saframycin A, makes them promising therapeutics, while their structural complexity and particularity provide challenging synthetic targets. These alkaloids or derivatives show interesting biological activity, but the most important drawback as potential market therapeutics is the minute amount of them available from nature, and the synthetic methods published are inconvenient, difficult, and hard to handle. Herein is described our researches about the tetrahydroisoquinoline alkaloids. Chapter 1 describes relevant background related to the biological significance of these alkaloids, and the currently synthetic studies toward these natural products. Chapter 2 describes our design and synthesis of the analogues based on the anticancer mechanism of the tetrahydroisoquinoline alkaloids, and the biological activities of these analogues. Chapter 3 describes a rapid synthetic route for the common structure of the bis-tetrahydroisoquinoline alkaloids via a controlled mono-Pictet-Spengler cyclization.

Table of Contents
Abbreviations……………………………………………………………………………………viii
Chapter 1: Tetrahydroisoquinoline Alkaloids.............................................................................1
1.0 Introduction ..................................................................................................................1
1.1 Biological Activity .......................................................................................................4
1.2 Mechanism of Action .................................................................................................12
1.3 Biosynthesis................................................................................................................15
1.4 Synthetic Approaches to Tetrahydroisoquinoline Alkaloids….……….……………17
1.4.1 Fukuyama’s Synthetic Studies…………………………….…………………18
1.4.1.1 First Total Synthesis of (±)-Saframycin B……..…......………………18
1.4.1.2 Total Synthesis of ET-743……………………..……………………..20
1.4.1.3 Synthetic Studies on (+)-Naphthyridinomycin..…...…………………25
1.4.1.4 Synthetic Studies on (-)-Lemonomycin………..……………………..27
1.4.2 Stoltz’s Synthetic Studies…………………………….…………………...…29
1.4.2.1 First Total Synthesis of (-)-Lemonomycin……..……………………..29
1.4.3 Magnus’s Synthetic Studies…………………………..……..……………….31
1.4.3.1 Synthetic Studies on 1,3-cis-Sbustituted Tetrahydroisoquinoline Core31
1.4.3.2 Total Synthesis of (±)-Renieramycin G…………….…...…………….33
1.4.4 Williams’s Synthetic Studies……………………………….………………..36
1.4.4.1 Synthetic Studies on Tetrahydroisoquinolind Alkaloids……….……..36
1.4.4.2 Total Synthesis of (-)-Renieramycin G………………………...……..38
1.4.4.3 Total Synthesis of (-)-Cribrostatin IV………………………………...40
1.4.5 Danishefsky’s Synthetic Studies……………………………………………..42
1.4.5.1 Total Synthesis of (-)-Cribrostatin IV………………………………...42
1.4.5.2 Formal Total Synthesis of ET-743………….…………………………46
1.4.6 Zhu’s Synthetic Studies….…………………………………………………...48
1.4.6.1 Total Synthesis of ET-743………..…………………………………...48
1.4.7 Avendaño’s Synthetic Studies………………………………………………..51
1.4.7.1 Synthetic Studies on Tetrahydroisoquinoline Alkaloids……………...51
1.4.8 Liu’s Synthetic Studies………………………………...…………...………...52
1.4.8.1 Synthesis of the Ecteinascidin-Saframycin Analogs………….………52
1.5 Conclusion…………………………………………………………………………..55
1.6 Reference……………………………………………………………………………56
Chapter 2: Design of the Anticancer Agent…………………………………………………..63
2.0 Introduction………………………………………………………………………….63
2.1 Analysis of the Tetrahydroisoquinoline Alkaloids………………..……………..…..64
2.2 Retrosynthesis of the Designed Analogues………………………………………….67
2.3 Results and Discussion………………………………………………………….…..68
2.3.1 Synthesis of the Designed Analogues….………………………………….....68
2.3.2 Bioactivities of the Designed Analogues………………….…………………79
2.4 Conclusion…………………………………………………………………………..84
2.5 Experimental Section…………..……………..……………………………………..85
2.5.1 General Information………………………………………………………….85
2.5.2 Synthesis……………………………………………………………………..86
2.6 Reference…………………………………………………………………………..104
Chapter 3: Synthetic Studies toward the Tetrahydroisoquinoline Alkaloids…..…………….105
3.0 Introduction………………………………………………………………………...105
3.1 Retrosynthesis of the Tetrahydroisoquinoline Alkaloids…………………………..106
3.2 Results and Discussion………………………………………………………….….107
3.2.1 Synthesis…………………………………………………….……………...107
3.2.2 Bioactivities of the Bridged Pentacyclic Analogues…..……………………115
3.3 Conclusion…………………………………………………………………………116
3.4 Experimental Section…………..……………..……………………………………117
3.4.1 General Information………………………………………………………...117
3.4.2 Synthesis……………………………………………………………………118
3.5 Reference…………………………………………………………………………..126

chapter 1
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Chapter 2
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Chapter 3
1. For a review, see: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669-1730.
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13. Crystallographic data for the structure have been deposited with the Cambridge Crystallographic Data Center under the following numbers: CCDC-646662.
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